Viruses are the etiologic cause of many life-threatening human diseases. Of special importance are the human immunodeficiency virus (HIV) and the hepatitis B virus (HBV).
In 1981, acquired immune deficiency syndrome (AIDS) was identified as a disease that severely compromises the human immune system, and that almost without exception leads to death. In 1983, the etiological cause of AIDS was determined to be the human immunodeficiency virus (HIV). According to the Joint United Nations Programme on HIV/AIDS, 40 million people are estimated to be living with HIV/AIDS at the end of 2006. During that same year, AIDS caused the deaths of an estimated 3 million people, and it was estimated that over 4 million people were infected by AIDS in 2006.
Another virus that causes a serious human health problem is the hepatitis B virus (referred to below as “HBV”). Hepatitis B virus (HBV) is a virus that causes chronic disease responsible for serious liver damage, including cirrhosis of the liver, cancer, organ failure and ultimately, death. HBV is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unknown. It is postulated that it may directly trigger tumor development, or indirectly trigger tumor development through chronic inflammation, cirrhosis, and cell regeneration associated with the infection. After a two to six month incubation period in which the host is unaware of the infection, HBV infection can lead to acute hepatitis and liver damage, that causes abdominal pain, jaundice, and elevated blood levels of certain enzymes. HBV can cause fulminant hepatitis, a rapidly progressive, often fatal form of the disease in which massive sections of the liver are destroyed. Patients typically recover from acute hepatitis. In some patients, however, high levels of viral antigen persist in the blood for an extended, or indefinite, period, causing a chronic infection. Chronic infections can lead to chronic persistent hepatitis. Patients infected with chronic persistent HBV are most common in developing countries. By mid-1991, there were approximately 225 million chronic carriers of HBV in Asia alone. It is estimated that approximately 300 million people worldwide are infected with HBV. The epidemiology of HBV is very similar to that of acquired immune deficiency syndrome, which accounts for why HBV infection is common among patients with AIDS or AIDS related complex. However, HBV is more contagious than HIV. Although use of a prophylactic vaccine has reduced the incidence of new HBV infections, there continues to be a need for an effective therapeutic drug. Various derivatives of nucleoside analogues have been found to exhibit antiviral activity. Notably, acyclovir (Zovirax) and its prodrug valacyclovir (Valtrex) are approved drugs for infections caused by HSV-1 and HSV-2. Acyclovir Therapy for Herpesvirus Infections (Baker, Ed.), M. Dekker, New York (1990); Against HCMV, four drugs are currently available: Ganciclovir (Cytovene), cidofovir (Vistide), antisense oligonucleotide fomivirsen (Vitravene) and foscarnet (Foscavir). However, only ganciclovir is effective orally but it requires large doses and produces potentially serious adverse effects such as bone marrow suppression. Ganciclovir Therapy for Cytomegalovirus Infection (Spector, S. S., Ed.), M. Dekker, New York (1991). A considerable effort went into design, synthesis and biological investigation of analogues of these drugs as well as in development of new antiviral agents. Larsson, A., et al., Antimicrob. Agents & Chemother. 30:598-605 (1986); Ashton, W. T., et al., J. Med. Chem. 31:2304-2315 (1988). Cidofovir and fomivirsen are approved only for topical application against retinitis in AIDS patients and foscarnet is used only by intravenous route and it leads to characteristic toxicity.
Current drugs for AIDS include AZT (zidovudine, Retrovir), ddI (didanosine, Videx), ddC (zalcitabine, Hivid) and d4T (stavudine, Zerit). De Clercq, E., J. Med. Chem. 38:2491-2517 (1995). Allenic nucleoside analogues such as adenallene and cytallene are examples of anti-HIV agents containing an unsaturated alkyl group. U.S. Pat. No. 4,935,427; Zemlicka, J., Allenols Derived from Nucleic Acid Bases—a New Class of Anti-HIV Agents: Chemistry and Biological Activity in Nucleosides and Nucleotides as Antitumor and Antiviral Agents (Chu, C. K.; Baker, D. C., Eds.), Plenum Press, New York, pp. 73-100 (1993). For HBV, alpha interferon and 3TC (lamivudine; Epivir) are two drugs licensed for the treatment of persons with chronic HBV infection. Unfortunately, only about 40% of patients respond to these drugs and resistance is a growing problem.
GILEAD is currently marketing two acyclic nucleotide phosphonate antiviral molecules: cidofovir or HPMC (VISTIDE®) against cytomegalovirus (CMV) and tenofovir or (R)-PMPA in the a pro-drug form (VIREAD®). Incidentally, tenofovir received FDA approval in October 2001 for monotherapy against HIV-1 and obtained an “AMM” [Market Authorization] in Europe in February 2002. It also developed adefovir or PMEA, for the treatment of HBV (HEPSERA®).
These compounds are also confronted to resistance problems. For example, it is recognized that the only mutation against Tenofovir directly selected at low frequency is the K65R mutation (Wainberg, M. A.; Miller, M. D.; Quan, Y.; Salomon, H.; Mulato, A. S.; Lamy, P. D.; Margot, N. A.; Anton, K. E.; Chemington, J. M. In vitro selection and characterization of HIV-1 with reduced susceptibility to PMPA. Antiviral Therapy 1999, 4, 87). However, it has been shown that thymidine analogue resistance mutations (TAMs) considerably reduce the effectiveness of Tenofovir when there are more than 3 mutations, preferentially with M41L and L210W, suggesting that the TAMs excise the Tenofovir. The excision of PMPA by the TAMs is a major point in the current resistance of HIV-1 associated with this compound (Miller, M. K65R, TAMS and tenofovir. AIDS Rev 2004, 6, 22).
However, the synthesis of such molecules in quantitative yields proves difficult. Thus, in light of the growing problems with viral resistance to the retrovirals used today, there remains a need to rapidly develop effective new antivirals.